Carbon monoxide (CO) is, by common definition, a colorless, odorless, tasteless, non-corrosive gas of about the same density as that of air and is the most commonly encountered and pervasive poison in our environment, it is generally produced by the incomplete combustion of fossil fuels such as natural gas, propane, coal, gasoline end wood. In the atmosphere, the average global levels are estimated to be 0.19 parts per million (p.p.m.), 90% of which comes from natural sources including ocean micro-organism production, and 10% or which is generated by human activity. Thus, inhalation of even small quantities of CO is inevitable for living organisms.
Depending on the extent and time of exposure, CO is capable of producing a myriad of debilitating and harmful residual effects to the organism (1). The most immediate of these effects, and perhaps the most notorious one, is binding to hemoglobin in the blood stream, which rapidly decreases the oxygen transport capability of the cardiovascular system. Paradoxically, more than half a century ago it was found that CO is constantly formed in human in small quantities (2), and that under certain pathophysiological conditions this endogenous production of CO may be considerably increased (3-5). The discovery that hemoglobin, a heme-dependent protein, is required as substrate for the production of CO in vivo (6, 7) and the identification of the enzyme heme oxygenase as the crucial pathway for the generation of this gaseous molecule in mammals (8) set the basis for the early investigation of an unexpected and still unrecognized role of CO in the vasculature (9). The succeeding cloning (10) and characterization of constitutive (HO-2) and inducible (HO-1) isoforms of heme oxygenase (11-13) as well as studies on the kinetics and tissue distribution of these enzymes (14) started to reveal a major importance of this pathway in the physiological degradation of heme. That is, the end products of heme degradation (CO, biliverdin and bilirubin) might possess, after all, crucial biological activities (15-17).
With regard to the cardiovascular system, the recognition that CO possesses vasodilatory properties (18-20) is, perhaps, the most significant evidence in favor of a pharmacological function of CO. Although the molecular mechanisms and the chemical modifications that are required to transduce the signals mediated by CO into a specific biological effect need to be fully elucidated, convincing scientific reports have recently highlighted the signaling properties of endogenously generated CO (21-24).
Experimental studies on the physiological effects of nitric oxide (NO) have been facilitated by the development of a wide variety of organic compounds that spontaneously release NO and can be easily acquired to reproduce a physiological or pathophysiological function of NO. There is now abundant literature on the different types of NO donors and NO-releasing agents that, depending on their stability and half-life, can be used in disparate in vitro and in vivo models to simulate the biological activity of this important signaling molecule (25, 26). In clinical practice, compounds that deliver NO into the circulation such as sodium nitroprusside and glyceryl trinitrate are used to lower blood pressure and treat certain cardiovascular diseases (27). Drugs containing a functional NO group that can selectively target an organ or tissue are currently being developed or are under clinical trials for the treatment of specific pathophysiological states (28, 29). However, to date no compounds capable of delivering CO therapeutically have been identified.
U.S. Pat. No. 5,882,674 proposes administration of CO via transdermal delivery systems containing metal carbonyl complexes such as iron pentacarbonyl and iron enneacarbonyl. However, since this document provides no experimental data, and no description of specific devices, it is not clear how this proposal can be made to work. In particular it is not stated whether the iron carbonyl complex is intended to be absorbed from the patch, to release CO within the body, or whether the complex breaks down within the patch to release CO which then enters the bloodstream after absorption through the skin. If, and to the extent that, this document is considered to make available pharmaceutical devices, compositions and methods for the practical and effective delivery of carbon monoxide in vivo, such devices, compositions and methods are excluded from the scope of the present invention.
Amongst literature relating to metal carbonyls, WO98/48848 describes facial metal tricarbonyl compounds and their use in the labelling of biologically active substrates. The metals, preferably radionuclides, are of Group 7, the metals identified being Mn, 99Tc, 186Re and 188Re. The compounds fac-[M(CO)3(OH2)3]+ where M is the metal are proposed for labelling of biologically active substrates, as a result of which metal carbonyl compounds having a variety of biologically active ligands are obtained. In the examples radioactive Tc is used. The document describes preparation of diagnostic and therapeutic compositions but no therapeutic composition is specifically disclosed, nor is any treatment of any condition by therapy mentioned. There is no disclosure of use of the compounds for delivering carbon monoxide to physiological targets. If, and to the extent that, this document is regarded as disclosing a therapeutic use or mode of therapeutic administration of the carbonyl compounds, that subject matter is excluded from the scope of the present invention. Preferably the present invention excludes use of the facial carbonyl compounds disclosed in this document in any event.
WO 91/01128 and WO 91/01301 describe compositions for treating skin to repair the effects of photoaging by topical application or to treat acne or psoriasis by topical or oral administration. The active compounds are polyene esters and iron carbonyl complexes thereof. Specifically the iron of iron tri-carbonyl is coordinated to the polyene chain. No reason for including the iron carbonyl is mentioned. Insofar as therapeutic uses or compositions of carbonyl compounds are disclosed in these two documents, such uses and compositions are specifically excluded from the scope of the present invention.
WO 98/29115 describes compositions and methods for relaxing smooth muscle in a warm-blooded animal by administering certain transition metal nitrosyl compounds. Treatments of hypertension, angina pectoris, congestive heart failure and impotence are mentioned.
Some of the compounds contain, in addition to NO, CO as a ligand. Specifically the CO-containing compound has the formula L3M(NO)yX3-y where L is a two-electron Lewis base or L3 is a six-electron Lewis base, M is a Group 6 or 8 transition metal and when y is 1, X is carbon monoxide. The essential teaching of this document is concerned with the therapeutic effect of nitrosyl complexes. There is no disclosure that the CO ligand, when present, has any therapeutic effect by delivery of CO to a physiological target. The CO-containing metal nitrosyl complexes disclosed in it are excluded from the novel metal carbonyls of the present invention and their uses for treatments mentioned are also excluded from the present invention. Preferably transition metal nitrosyl complexes containing CO are excluded from the scope of the present invention in any event.
HU-B-211084 describes a composition, which is for oral administration, for the fortification of bones containing calcium phosphate, at least one calcium salt of an organic acid and optionally iron pentacarbonyl. The present invention does not extend to the use of iron pentacarbonyl in combination with calcium compounds as specified in this document in connection with the therapeutic uses and modes of administration described there, and preferably does not extend to the use of iron carbonyls and complexes including iron and CO in combination with calcium phosphates and/or calcium salts of organic acids in any event.
WO 95/05814 (U.S. Pat. No. 6,284,752) and WO 00/56743 both disclose a very wide range of metal complexes, for use in treatment of disease relating to the overproduction of reactive oxygen species, particularly overproduction of NO. The stated aim is to modulate NO levels in the body by scavenging, or removing, NO in situ. The ex-vivo test data are stated to show that vasoconstriction is a direct result of the removal of endogenous nitric oxide. Carbon monoxide is mentioned as a possible ligand, but no example of a complex containing carbon monoxide is given and no effect is attributed to CO. Insofar as these documents are considered to disclose practical use of a complex containing CO for the specified purpose, such use does not form part of the present invention.